ZA200407235B - Sulfonylamino-derivatives as novel inhibitors of histone deacetylase. - Google Patents

Sulfonylamino-derivatives as novel inhibitors of histone deacetylase. Download PDF

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ZA200407235B
ZA200407235B ZA200407235A ZA200407235A ZA200407235B ZA 200407235 B ZA200407235 B ZA 200407235B ZA 200407235 A ZA200407235 A ZA 200407235A ZA 200407235 A ZA200407235 A ZA 200407235A ZA 200407235 B ZA200407235 B ZA 200407235B
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South Africa
Prior art keywords
galkyl
salkyl
aminoc
amino
4alkyl
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ZA200407235A
Inventor
Kristof Van Emelen
Sven Franciscus Anna Va Brandt
Isabelle Noelle Consta Pilatte
Hans Louis Jos De Winter
Leo Jacobus Jozef Backx
Angibaud Jozef
Rene Patrick
Marc Gustaaf Celine Verdonck
Jimmy Arnold Viviane V Heusden
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Janssen Pharmaceutica Nv
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Publication of ZA200407235B publication Critical patent/ZA200407235B/en

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Description

SULFONYLAMINO-DERIVATIVES AS NOVEL INHIBITORS OF HISTONE
DEACETYLASE.
This invention concerns compounds having histone deacetylase (HDAC) inhibiting . enzymatic activity. It further relates to processes for their preparation, to compositions comprising them, as well as their use, both in vitro and in vivo, to inhibit HDAC and as a medicine, for instance as a medicine to inhibit proliferative conditions, such as cancer and psoriasis.
In all eukaryotic cells, genomic DNA in chromatine associates with histones to form nucleosomes. Each nucleosome consists of a protein octamer made up of two copies of each histones H2A, H2B, H3 and H4. DNA winds around this protein core, with the basic amino acids of the histones interacting with the negatively charged phosphate groups of the DNA. The most common posttranslational modification of these core histones is the reversible acetylation of the e-amino groups of conserved, highly basic
N-terminal lysine residues. The steady state of histone acetylation is established by the dynamic equilibrium between competing histone acetyltransferase(s) and histone deacetylase(s) herein referred to as “HDAC”. Histone acetylation and deacetylation has long been linked to transcriptional control. The recent cloning of the genes encoding different histone acetyltransferases and histone deacetylases provided a possible explanation for the relationship between histone acetylation and transcriptional control.
The reversible acetylation of histones can result in chromatin remodelling and as such act as a control mechanism for gene transcription. In general, hyperacetylation of histones facilitates gene expression, whereas histone deacetylation is correlated with transcriptional repression. Histone acetyltransferases were shown to act as transcriptional coactivators, whereas histone deacetylases were found to belong to transcriptional repression pathways.
The dynamic equilibrium between histone acetylation and deacetylation is essential for normal cell growth. Inhibition of histone deacetylase results in cell cycle arrest, cellular differentiation, apoptosis and reversal of the transformed phenotype. Therefore HDAC inhibitors can have great therapeutic potential in the treatment of cell proliferative - diseases or conditions (Marks et al., Nature Reviews: Cancer 1: 194-202, 2001) . 35 The study of inhibitors of histone deacetylases (HDAC) indicates that indeed these enzymes play an important role in cell proliferation and differentiation. The inhibitor
Trichostatin A (TSA) causes cell cycle arrest at both G1 and G2 phases, reverts the transformed phenotype of different cell lines, and induces differentiation of Friend leukemia cells and others. TSA (and suberoylanilide hydroxamic acid SAHA) have been reported to inhibit cell growth, induce terminal differentiation, and prevent the formation of tumours in mice (Finnin et al., Nature, 401: 188-193, 1999). Trchostatin A has also been reported to be useful in the treatment of fibrosis, e.g. liver . fibrosis and liver chirrhosis. (Geerts et al., European Patent Application EP 0 827 742, published 11 March, 1998).
Patent application WO01/38322 published on May 31, 2001 discloses amongst others inhibitors of histone deacetylase of general formula Cy-L'-Ar-Y'-C(0)-NH-Z, providing compositions and methods for treating cell proliferative diseases and conditions.
Patent application WO01/70675 published on 27 September, 2001 discloses inhibitors of histone deacetylase of formula Cy-S(0),-NH-Y>-W and further provides compositions and methods for treating cell proliferative diseases and conditions.
The problem to be solved is to provide histone deacetylase inhibitors with high enzymatic activity and also show advantageous properties such as cellular activity and increased bioavailability, preferably oral bioavailability, and have little or no side effects.
The novel compounds of the present invention solve the above-described problem. The compounds differ from the prior art in structure.
The compounds of the present invention show excellent in-vitro histone deacetylase inhibiting enzymatic activity. The present compounds have advantageous properties with regard to cellular activity and specific properties with regard to inhibition of cell cycle progression at both G1 and G2 checkpoints (p21 induction capacity). The compounds of the present invention show good metabolic stability and high bioavailability and more particular they show oral bioavailability. Moreover, the compounds of the present invention have a low affinity for the P450 enzymes, which - reduces the risk of adverse drug-drug interaction allowing also for a wider safety margin.
This invention concerns compounds of formula (I)
RE en, al . )—N Z— (CRY) N— 0)
Na aC . R? the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo- chemically isomeric forms thereof, wherein nis 0, 1, 2 or 3 and when nis O then a direct bond is intended; tisO, 1, 2,3 or 4 and when t is O then a direct bond is intended; each Q is nitrogen or -s ; — each X is nitrogen or ~N,
Pe each Y is nitrogen or ~ ; oo —CHT each Z is nitrogen or ~;
R'is —C(O)NR®R®, -N(H)C(O)R'?, -C(0)-C, salkanediylSR'?, -NR''C(O)N(OH)R'°,
NR!'C(0)C salkanediylSR'®, -NR''C(0)C=N(OH)R'’ or another Zn-chelating- group wherein R® and R® are each independently selected from hydrogen, hydroxy,
C,.¢alkyl, hydroxyCj.¢alkyl, aminoCj.¢alkyl or aminoaryl;
R'? is independently selected from hydrogen, Cy.salkyl, Ci calkylcarbonyl, arylCj_ealkyl, Ci.galkylpyrazinyl, pyridinone, pyrrolidinone or methylimidazolyl;
R'is independently selected from hydrogen or Cj alkyl;
R? is hydrogen, halo, hydroxy, amino, nitro, Cy.salkyl, C,.¢alkyloxy, trifluoromethyl, di(C,.alkyl)amino, hydrox yamino or naphtalenylsulfonylpyrazinyl; each R® independently represents a hydrogen atom and one hydrogen atom can be ’ replaced by a substituent selected from aryl; R*is hydrogen, hydroxy, amino, hydroxyC,_salkyl, C,.6alkyl, Ci.galkyloxy, arylC,_galkyl, aminocarbonyl, hydrox ycarbonyl, aminoCj_galkyl,
aminocarbonylC_galkyl, hydroxycarbonylC,_galkyl, hydroxyaminocarbonyl,
Cj.¢alkyloxycarbonyl, Cy.galkylaminoC,.galkyl or di(C;_galkyl)aminoCj galkyl; i Ris hydrogen, Cy.galkyl, Cs.iocycloalkyl, hydroxyCj_galkyl, Ci galkyloxyC)_ealkyl, di(C,.¢alky)aminoC, _galkyl or aryl; oO is a radical selected from val veh ah vai
S N, X/
SF ZF FF
(a-1) (a-2) (a-3) (a-4) bY R"), Ns Ns
A N y 17 NH L_o ~~ (a-5) (2-6) @7) (2-8)
Ns R'); b% 7s
S, S, 0, 0, N (a-9) (a-10) (a-11) (a-12) 7 )
I * ’ / y vai y Yah
ON ; ’ N. ) i —\ — —J \ / \ ) ] (a-13) (a-14) (a-15) (a-16) . 7 | R®)
Sy YY A
SS JI CUTAN SWeR Ue \—/ / “NA A
N NH 0 \—y Ss (a-17) (2-18) N @l19) “SN (2-20)
%s R's Ms Ms 7 l/ Ns Yar Nx O®
FF aC N (a-21) (a-22) (3-23) (2-24) [3 Rr’
Ns bX Js u )s ve ~ 7 7 N~" ” 0 an <x ~zN a (a-25) 026 (a-27) (a-28)
Ms Wok Walk La
S SA YO,
Yo On UG
NT #0 ZN o
H
(a-29) (2-30) (a-31) (2-32) 7 7 ®")s ®R") 0 ®"; \ )s or 40 0
Cr 7° A J NTS
N
H
(a-34) (2-35) (a-36) @39 7 7 7
Ds ve Js ve )s va s > O. bh vr, UD
PN FZ SF Z
N No N (a-37) (2-38) (a-39) (a-40) : Lo 0 LL Va 3 NLA
S Z N N
Pa Nao - (a-41) (2-42) (2-43) (a-44) 7 D) LY 0 R'); 0 RY) i S ve s
Vr vo YO YD
NH p: P
Ne =N Ny SN N (a-45) (a-46) (a-47) (a-48)
R); Rs Ms
YE GN, x | X | NPL (a-49) (a-50) (a-51) wherein each s is independently 0, 1, 2, 3, 4 or 5; each R® and R’ are independently selected from hydrogen; halo; hydroxy; amino; nitro; trihaloC alkyl; trihaloC_¢alkyloxy; Cj galkyl; C_salkyl substituted with aryl and
Cs.10cycloalkyl; Cy galkyloxy; Cj.¢alkyloxyCj.galkyloxy; C 1-salkylcarbonyl,
C-salkyloxycarbonyl; C;_galkylsulfonyl; cyanoC,_galkyl; hydroxyC,_galkyl; hydroxyCj_salkyloxy; hydrox yC;_salkylamino; aminoCj_galkyloxy; di(Cj_¢alkyl)aminocarbonyl; di(hydroxyCj.salkyl)amino; (aryl)(C;_galkyl)amino; di(Cy_gsalkyl)aminoCj.galkyloxy, di(Cj_galkyl)aminoCj_galkylamino; di(Cy.¢alkyl)aminoC,.¢alkylaminoCj.galkyl; arylsulfonyl; arylsulfonylamino; aryloxy; aryloxyCj_galkyl; arylC,_ galkenediyl; di(Cj.galkyl)amino; di(C;.¢alkyl)aminoCy_galkyl; di(C;_ealkyl)amino(C;.galkyl)amino; di(C.¢alkyl)amino(C,.galkyl)aminoC_galkyl; di(C_ealkyl)aminoC,_galkyl(C;_galkyl)amino; di(C).galkyl)aminoC;_galkyl(C;_galkyl)aminoC;.galkyl; aminosulfonylamino(C;_galkyl)amino; aminosulfonylamino(C;_galkyl)aminoC;_galkyl; di(Cj.galkyl)aminosulfonylamino(C;_galkyl)amino; di(C.¢alkyl)aminosulfonylamino(C;_¢alkyl)aminoC.galkyl; cyano; thiophenyl; thiophenyl substituted with di(C,.¢alkyl)aminoC_galkyl(C,_galkyl)aminoC_galkyl, di(C,_salkyl)aminoC_galkyl, Cj.ealkylpiperazinylCy_galkyl, hydroxyCj_ealkylpiperazinylC_galkyl, hydroxyCj_galkyloxyCy.salkylpiperazinylCj_galkyl, di(C.salkyl)aminosulfonylpiperazinylCj_galkyl,
Ci.¢alkyloxypiperidinyl, Cy.¢alkyloxypiperidinylC,_galkyl, morpholinylC; galkyl, hydroxyC,_ealkyl(Cj.salkyl)aminoC,.galkyl, or dithydroxyCj_galkyl)aminoC,.galkyl; furanyl; furanyl substituted with hydroxyCj_alkyl; benzofuranyl; imidazolyl, . oxazolyl; oxazolyl substituted with aryl and C,.galkyl; C_galkyltriazolyl; tetrazolyl, pyrrolidinyl; pyrrolyl; piperidinylC_galkyloxy; morpholinyl; Ci.¢alkylmorpholinyl; } morpholinylC, ¢alkyloxy; morpholinylC,_galkyl; morpholinylC;_galkylamino; morpholinylC; galkylaminoC,_galkyl; piperazinyl; Cy.galkylpiperazinyl;
Ci.ealkylpiperazinylC)_alkyloxy; piperazinylC,_galkyl; naphtalenylsulfonylpiperazinyl; naphtalenyisulfonylpiperidinyl; naphtalenylsulfonyl;
C,.ealkylpiperazinylCy_galkyl; Cj galkylpiperazinylC, galkylamino;
C,.¢alkylpiperazinylC _¢alkylaminoC,_galky!; Ci.galkylpiperazinylsulfonyl, aminosulfonylpiperazinylCj.galkyloxy; aminosulfonylpiperazinyl; : aminosulfonylpiperazinylC_galkyl; di(C;.¢alkyl)aminosulfonylpiperazinyi;
S di(C).galkyl)aminosulfonylpiperazinylC,.galkyl; hydroxyCj_galkylpiperazinyl; . hydroxyC)_galkylpiperazinylC,.galkyl; C;_salkyloxypiperidinyl;
C;.¢alkyloxypiperidinylCy_galkyl; piperidinylaminoCy.¢alkylamino; : piperidinylaminoCj_galkylaminoCj_ alkyl; (C,.¢alkylpiperidinyl)(hydroxyC.salkyl)aminoCj.¢alkylamino; (C1.salkylpiperidinyl)(hydroxyC,.salkyl)aminoC;_galkylaminoC,_galkyl; hydroxyCj_salkyloxyC.ealkylpiperazinyl; hydroxyC)_¢alkyloxyC;.ealkylpiperazinylC.ealkyl; (hydrox yCj.¢alkyl)(C.galkyl)amino; (hydrox yCj_¢alkyl)(C;.¢alkyl)aminoCj.galkyl, hydroxyC;.galkylaminoCj.galkyl; di(hydroxyCj.salkyl)aminoC .alkyl; pyrrolidinylCy_galkyl; pyrrolidinylC,_galkyloxy; pyrazolyl; thiopyrazolyl; pyrazolyl substituted with two substituents selected from Cj_galkyl or trihaloC;_galkyl; pyridinyl; pyridinyl substituted with C;_salkyloxy, aryloxy or aryl; pyrimidinyl; tetrahydropyrimidinylpiperazinyl; tetrahydropyrimidinylpiperazinylCy_galkyl; quinolinyl; indole; phenyl; phenyl substituted with one, two or three substituents independently selected from halo, amino, nitro, Cy.¢alkyl, C;.¢alkyloxy, hydrox yCj_4alkyl, trifluoromethyl, trifluoromethyloxy, hydroxyCi.salkyloxy,
C).salkylsulfonyl, C_4alkyloxyCj_salkyloxy, Cj.4alkyloxycarbonyl, aminoCj.salkyloxy, di(C;.salkyl)aminoC)_salkyloxy, di(C;_salkyl)amino, di(C_salkyl)aminocarbonyl, di(Cj.salkyl)aminoCi.salkyl, di(C;_4alkyl)aminoC,;_4alkylaminoC;_salkyl, di(C.4alkyl)amino(Cj_4alkyl)amino, di(Cj.salkyl)amino(C_salkyl)aminoC.4alkyl, di(C.salkyl)aminoC;.4alkyl(C_salkyl)amino, di(C).4alkyl)aminoC_salkyl(C,.salkyl)aminoC,_salkyl, aminosulfonylamino(C;.4alkyl)amino, aminosulfonylamino(C.4alkyl)aminoCj_salkyl, di(Cj_salkyl)aminosulfonylamino(C;.salkyl)amino, di(C,.4alkyl)aminosulfonylamino(C,_salkyl)aminoC,.galkyl, cyano, ’ piperidinylCy_4alkyloxy, pyrrolidinylCy_salkyloxy, aminosulfonylpiperazinyl, aminosulfonylpiperazinylCj_4alkyl, di(C;.4alkyl)aminosulfonylpiperazinyl, : 35 di(C-salkyl)aminosulfonylpiperazinylC;.4alkyl, hydrox yCi_salkylpiperazinyl, hydroxyCj_salkylpiperazinylC,_salkyl, C}_salkyloxypiperidinyl,
C,_salkyloxypiperidinylCy_qalkyl, hydroxyC,.salkyloxyCy_salkylpiperazinyl, hydroxyCj.salkyloxyC_salkylpiperazinylC,_salkyl,
(hydroxyCi.4alkyl)(C,.4alkyl)amino, (hydroxyCj.4alkyl)(C,;_salkyl)aminoC_saikyl, di(hydroxyCj_salkyl)amino, di(hydroxyC;_salkyl)aminoC,_salkyl, furanyl, furanyl substituted with -CH=CH-CH=CH-, pyrrolidinylC;_4alkyl, pyrrolidinylC,_salkyloxy, i morpholinyl, morpholinylC, salkyloxy, morpholinylC;_salkyl, morpholinylC;_salkylamino, morpholinylC,_4alkylaminoC_jalkyl, piperazinyl,
Cj.aalkylpiperazinyl, C_salkylpiperazinylC;_4alkyloxy, piperazinylC,_salkyl,
C).qalkylpiperazinylCi_4alkyl, C;_salkylpiperazinylC_4altkylamino,
Cj.salkylpiperazinylCj_salkylaminoC,_galkyl, tetrahydropyrimidinylpiperazinyl, tetrahydropyrimidinylpiperazinylCj_salkyl, piperidinylaminoC,_salkylamino, piperidinylaminoC;_salkylaminoC, 4alkyl, (C.4atkylpipendinyl)(hydroxyC, salkyl)aminoC;_4alkylamino, (Cj-salkylpiperidinyl)(hydroxyC,_salkyl)aminoC; 4alkylaminoC,_salkyl, pyridinylC,_salkyloxy, hydroxyCj.salkylamino, hydroxyCi.salkylaminoC; alkyl, di(C,_salkyl)aminoC,.4alkylamino, aminothiadiazolyl, aminosulfonylpiperazinylC;_4alkyloxy, or thiophenylC,_salkylamino; each R® and R’ can be placed on the nitrogen in replacement of the hydrogen; aryl in the above is phenyl, or phenyl substituted with one or more substituents each independently selected from halo, C,_galkyl, C;salkyloxy, trifluoromethyl, cyano or hydroxycarbonyl.
The term “histone deacetylase inhibitor” or “inhibitor of histone deacetylase” is used to identify a compound, which is capable of interacting with a histone deacetylase and inhibiting its activity, more particularly its enzymatic activity. Inhibiting histone deacetylase enzymatic activity means reducing the ability of a histone deacetylase to remove an acetyl group from a histone. Preferably, such inhibition is specific, i.e. the histone deacetylase inhibitor reduces the ability of a histone deacetylase to remove an acetyl group from a histone at a concentration that is lower than the concentration of the inhibitor that is required to produce some other, unrelated biological effect.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C, ,alkyl defines straight and branched chain saturated hydrocarbon ’ radicals having from 1 to 4 carbon atoms such as, e.g. methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl and the like; C, (alkyl includes C, alkyl and the higher homologues thereof having 5 to 6 carbon atoms such as, for example, pentyl, 2-methyl- butyl, hexyl, 2-methylpentyl and the like; C, alkanediyl defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl 1,4-butanediyl,
1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof such as, 2- methylpentanediyl, 3-methylpentanediyl, 2,2-dimethylbutanediyl, 2,3- dimethylbutanediy! and the like; trihaloC; alkyl defines C, salkyl containing three : identical or different halo substituents for example trifluoromethyl; C, calkenediyl defines bivalent straight and branched chain hydrocarbon radicals containing one : double bond and having from 2 to 6 carbon atoms such as, for example, ethenediyl, 2-propenediyl, 3-butenediyl, 2-pentenediyl, 3-pentenediyl, 3-methyl-2-butenediyl, and the like; aminoaryl defines aryl substituted with amino; and Cs.jocycloalkyl includes cyclic hydrocarbon groups having from 3 to 10 carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl and the like.
The term “another Zn-chelating group” refers to a group, which is capable of interacting with a Zn-ion, which can be present at an enzymatic binding site.
Pharmaceutically acceptable addition salts encompass pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms, which the compounds of formula (I) are able to form. The compounds of formula (I) which have basic properties can be converted in their pharmaceutically acceptable acid addition salts by treating said base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, trifluoroacetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-amino-salicylic, pamoic and the like acids.
The compounds of formula (I) which have acidic properties may be converted in their pharmaceutically acceptable base addition salts by treating said acid form with a suitable organic or inorganic base. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, ’ potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such : 35 as, for example, arginine, lysine and the like.
The term “acid or base addition salts” also comprises the hydrates and the solvent addition forms, which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
The term “stereochemically isomeric forms of compounds of formula (I)”, as used herein, defines all possible compounds made up of the same atoms bonded by the same . sequence of bonds but having different three-dimensional structures, which are not interchangeable, which the compounds of formula (I) may possess. Unless otherwise : mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms, which said compound might possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of formula (I) both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.
The N-oxide forms of the compounds of formula (I) are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide, particularly those N-oxides wherein one or more of the piperidine-, piperazine or pyridazinyl-nitrogens are N-oxidized.
Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
Whenever used hereinafter, the term "compounds of formula (I)" is meant to include also the pharmaceutically acceptable addition salts and all stereoisomeric forms.
As used herein, the terms “histone deacetylase” and “HDAC” are intended to refer to any one of a family of enzymes that remove acetyl groups from the €-amino groups of lysine residues at the N-terminus of a histone. Unless otherwise indicated by context, the term “histone” is meant to refer to any histone protein, including H1, H2A, H2B,
H3, H4, and HS, from any species. Human HDAC proteins or gene products, include, but are not limited to, HDAC-1, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6,
HDAC-7, HDAC-8, HDAC-9 and HDAC-10. The histone deacetylase can also be derived from a protozoal or fungal source.
A first group of interesting compounds consists of those compounds of formula (I) ’ 35 wherein one or more of the following restrictions apply: a)nis 0, 1 or 2; b)tisO, 1,2 or 3; c)each Qis —< ;
d)R' is ~C(O)NH(OH) or -NR''C(0)C=N(OH)R'’ wherein R'is arylC, salkyl and R*’ is hydrogen; e) R? is hydrogen, Calkyl or naphtalenylsulfonylpyrazinyl; : f) each R® independently represents a hydrogen atom, g R* is hydrogen, hydroxy, hydroxyC_galkyl or C).¢alkyloxy; : h) R’ is hydrogen, Cy.¢alkyl, hydroxyCj.¢alkyl or Cy _galkyloxyCy.galkyl; 1) —(® is a radical selected from (a-1), (a-7) or (a-20); j) each s is independently O or 1; k) each R® is independently selected from hydrogen; thiophenyl; furanyl; benzofuranyl; phenyl; or phenyl substituted with one substituents independently selected from
Ci.6alkyl, Cj.ealkyloxy, hydroxyC,_4alkyl, Cj4alkylsulfonyl or di(C;.4alkyl)amino; 1) each R’ is independently selected from hydrogen.
A second group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply: a)ynis 1lor2; b)tis0,1,20r3; c)each Qs —K d) R' is -C(O)NH(OH), e)RZis hydrogen or Cyealkyl; f) each R? independently represents a hydrogen atom; g) R* is hydrogen; h) R’ is hydrogen or Cj.galkyloxyCj_galkyl; : 1) —® is a radical selected from (a-1) or (a-20); j)each sis independently O or 1; k) each RC is independently selected from hydrogen; thiophenyl; furanyl; benzofuranyl; phenyl; or phenyl substituted with one substituents independently selected from
Ci.ealkyl, Cy.galkyloxy, hydroxyCi.4alkyl or di(C;_4alkyl)amino.
A third group of interesting compounds consists of those compounds of formula (I) wherein R? is hydrogen.
A fourth group of interesting compounds consists of those compounds of formula (I) wherein. R' is ~C(O)NH(OH).
A fifth group of interesting compounds consists of those compounds of formula (I) wherein R' is -C(O)NH(OH) and R? is hydrogen.
A sixth group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply: . a)tis 0; 5b) R'is -C(O)NR®R’, -C(0)-C; salkanediylSR'’, -NR''C(O)N(OH)R"”, -NR''C(0)C, ¢alkanediylSR'®, -NR''C(O)C=N(OH)R '’ or another Zn-chelating- group wherein R® and R’ are each independently selected from hydrogen, hydroxy, hydroxyCgalkyl or aminoC,_galkyl, ¢) R?is hydrogen, halo, hydroxy, amino, nitro, Cy.salkyl, Cj.salkyloxy, trifluoromethyl or di(Cj.¢alkyl)amino; d) R* is hydrogen, hydroxy, amino, hydroxyCj_galkyl, C;_galkyl, Cj.galkyloxy, arylCy_galkyl, aminocarbonyl, aminoCj_ealkyl, Cj salkylaminoC;_galkyl or di(C,.galkyl)aminoC,_galkyl; e)R®is hydrogen f) —® is a radical selected from (a-1), (a-3), (a-4), (2-5), (a-6), (2-7), (a-8), (a-9), (a-10), (a-11), (2-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (2-19), (2-20), (a-21), (2-22), (a-23), (a-24), (a-25), (a-26), (a-28), (a-29), (a-30), (2-31), (2-32), (a-33), (a-34), (a-35), (a-36), (a-37), (2-38), (a-39), (a-40), (a41), (a-42), (2-44), (a-45), (a-46), (a-47), (a-48) or (a-51); g) each s is independently 0, 1, 2, 3 or 4; h) RS is hydrogen; halo; hydroxy; amino; nitro; trihaloC; alkyl; trihaloC,_galkyloxy;
C,.¢alkyl; Cygalkyloxy; Ci_galkylcarbonyl; Cy_galkyloxycarbonyl,
Cj.salkylsulfonyl; hydroxyCj.galkyl; aryloxy; di(C;.¢alkyl)amino; cyano; thiophenyl; furanyl; furanyl substituted with hydroxyCj.salkyl; benzofuranyl; imidazolyl; oxazolyl; oxazolyl substituted with aryl and Cj_galkyl;
Cy.¢alkyltriazolyl; tetrazolyl; pyrrolidinyl; pyrrolyl; morpholinyl;
C).salkylmorpholinyl; piperazinyl; C;_salkylpiperazinyl, hydroxyC, _galkylpiperazinyl; C;_galkyloxypiperidinyl; pyrazoly; pyrazolyl substituted with one or two substituents selected from Cj_galkyl or trihaloC_galkyl; pyridinyl; pyridinyl substituted with Cy.galkyloxy, aryloxy or aryl; pyrimidinyi; ] quinolinyl; indole; phenyl; or phenyl substituted with one or two substituents independently selected from halo, C).galkyl, C;_galkyloxy or trifluoromethyl; i) R7 is hydrogen; halo; hydroxy; amino; nitro; trihaloCy_galkyl; trihaloCy.galkyloxy;
Ci.6alkyl; Cj.galkyloxy; C).ealkylcarbonyl; C)_galkyloxycarbonyl;
C.¢alkylsulfonyl; hydroxyCy alkyl; aryloxy; di(C_galkyl)amino; cyano; pyndinyl; phenyl; or phenyl substituted with one or two substituents independently selected from halo, Cy.galkyl, Cy.galkyloxy or trifluoromethyl.
A seventh group of interesting compounds consists of those compounds of formula (I) : wherein one or more of the following restrictions apply: a) R® and R? are each independently selected from hydrogen, hydroxy, hydroxyCj.salkyl, aminoC,_galkyl or aminoaryl; b) R’ is hydrogen, C;.salkyl, Cjs.10cycloalkyl, hydroxyCy.galkyl, C.salkyloxyCj.galkyl or di(C;.¢alkyh)aminoCj.galkyl; c) —® is a radical selected from (a-1), (a-2), (2-3), (a-4), (a-5), (a-6), (a-7), (a-8), (2-9), (a-10), (a-11), (a-12), (a-13), (a-14), (2-15), (a-16), (a-17), (2-18), (2-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (2-27), (2-28), (2-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (2-37), (2-38), (a-39), (2-40), (a-41), (a-42) (a-43) or (a-44); d) each R® and R’ are independently selected from hydrogen; halo; hydroxy; amino; nitro; trihaloC.galkyl; trihaloCy.galkyloxy; C,.¢alkyl; Cj alkyloxy;
C;.¢alkyloxyCj.¢alkyloxy; C.ealkylcarbonyl; Cy.galkylsulfonyl; cyanoCj.galkyl; hydroxyCj.salkyl; hydroxyCi.ealkyloxy; hydroxyCj_salkylamino; aminoCj_galkyloxy; di(C,.galkyl)aminocarbonyl; di(hydroxyCj.¢alkyl)amino; arylC;_galkyl)amino; di(Cy.alkyl)aminoCy.salkyloxy; di(C;.galkyl)aminoCj_galkylamino; arylsulfonyl; arylsulfonylamino; aryloxy; arylC,.¢alkenediyl; di(C,.salkyl)amino; di(C.alkyl)aminoCi.galkyl; di(Cy.¢alkyl)aminoCj_ealkyl(C, _ealkyl)aminoC_ealkyl; cyano; thiophenyl; thiophenyl substituted with di(Cy salkyl)aminoCy.ealkyl(Cy.ealkyl)aminoCy.galkyl, di(C,.ealkyl)aminoCj.galkyl,
C;.¢alkylpiperazinylC.galkyl or di(hydroxyCj.ealkyl)aminoCy_galkyl; furanyl, imidazolyl; C).¢alkyltriazolyl; tetrazolyl; pyrrolidinyl; piperidinylCy.¢alkyloxy; morpholinyl; C.¢alkylmorpholinyl; morpholinylCy.salkyloxy; morpholinylCy.ealkyl; C.¢alkylpiperazinyl, C,.¢alkylpiperazinylCj.salkyloxy;
C,.¢alkylpiperazinylCy_galkyl; C,.¢alkylpiperazinylsulfonyl; } aminosulfonylpiperazinylC,_galkyloxy; aminosulfonylpiperazinyl; aminosulfonylpiperazinylC, galkyl; di(C;.¢alkyl)aminosulfonylpiperazinyl; di(C.galkyl)aminosulfonylpiperazinylCi.galkyl; hydroxyC).ealkylpiperazinyl; hydroxyCj.galkylpiperazinylCy.galkyl; C,.¢alkyloxypiperidinyl;
C,.¢alkyloxypiperidinylC, alkyl; hydrox yC.galkyloxyC, _salkylpiperazinyl; hydroxyC.salkyloxyC.galkylpiperazinylCj.galkyl;
WQ 03/076401 PCT/EP03/02517 (hydroxyCi_ealkyl)}(Ci.galkyl)amino; (hydroxyCi_galkyl)(Cy.¢alkyl)aminoC.galkyl; pyrrolidinylCj_galkyloxy; pyrazolyl; thiopyrazolyl; pyrazolyl substituted with two substituents selected from Cj.galky! or trihaloC_galkyl; pyridinyl; pyridinyl . substituted with Cy_galkyloxy or aryl; pyrimidinyl; quinolinyl; indole; phenyl; phenyl substituted with one, two or three substituents independently selected from halo, i amino, C;.¢alkyl, C1.ealkyloxy, hydroxyC)_salkyl, trifluoromethyl, trifluoromethyloxy, hydroxyCj_salkyloxy, Ci.salkyloxyCj.4alkyloxy, aminoC;_salkyloxy, di(C.4alkyl)aminoC)_salkyloxy, di(C,.salkyl)amino, di(C4alkyl)aminoC;.salkyl, di (C,4alkyl)aminoC_.4alkyl(C.salkyl)aminoCy.salkyl, piperidinylC;_alkyloxy, pyrrolidinylCy_salkyloxy, aminosulfonylpiperazinyl, aminosulfonylpiperazinylC,_4alkyl, di(C,.salkyl)aminosulfonylpiperazinyl, di(C;salkyl)aminosulfonylpiperazinylCi.qalkyl, hydroxyC)_4alkylpiperazinyl, hydroxyCj.4alkylpiperazinylC)_4alkyl, C,.salkyloxypiperidinyl,
C.salkyloxypiperidinylCi_4alkyl, hydroxyC;_salkyloxyCi.salkylpiperazinyl, hydroxyC_salkyloxyCj_salkylpiperazinylCj_salkyl, (hydroxyCj._salkyl)(Cy.salkyl)amino, (hydroxyCj_4alkyl)(Ci-satkyl)aminoCy_4alkyl, pyrrolidinylC,;_salkyloxy, morpholinylC_salkyloxy, morpholinylCy alkyl,
C,.salkylpiperazinyl, Cy.qalkylpiperazinylCy_galkyloxy,
C.qalkylpiperazinylCy_galkyl, hydroxyCj_salkylamino, di(hydroxyCj.4alkyl)amino, di(C;.salkyl)aminoCj.4alkylamino, aminothiadiazolyl, aminosulfonylpiperazinylCj_salkyloxy, or thiophenylC,.4alkylamino.
A group of preferred compounds consists of those compounds of formula (I) wherein R® and R’ are each independently selected from hydrogen, hydroxy, hydroxyCj.salkyl, aminoC;.galkyl or aminoaryl;
R® is hydrogen, C.galkyl, Cs.jocycloalkyl, hydroxyCj.galkyl, Cy.salkyloxyCj.ealkyl or di(C;.¢alkyl)aminoC.ealkyl, —® is a radical selected from (a-1), (a-2), (a-3), (a-4), (2-5), (a-6), (a-7), (a-8), (2-9), (a-10), (a-11), (a-12), (a-13), (a-14), (2-15), (a-16), (2-17), (a-18), (a-19), (a-20), (2-21), (2-22), (2-23), (a-24), (2-25), (2-26), (2-27), (a-28), (a-29), (a-30), } (a-31), (a-32), (a-33), (2-34), (2-35), (2-36), (2-37), (2-38), (a-39), (a-40), (a-41), (a-42) (a-43) or (a-44); } each R® and R’ are independently selected from hydrogen; halo; hydroxy; amino; nitro; trihaloC_galkyl; trihaloC_galkyloxy; Ci.ealkyl; Ci.ealkyloxy;
C;.¢alkyloxyCj_galkyloxy; Cy.galkylcarbonyl; C,.¢alkylsulfonyl; cyanoC,_galkyl, hydroxyCj.ealkyl; hydroxyCj_galkyloxy; hydroxyCj_salkylamino;
aminoC.galkyloxy; di(Cy.galkyl)aminocarbonyl; di(hydroxyC,_galkyl)amino; arylC,_galkyl)amino; di(C.¢alkyl)aminoC; ealkyloxy; di(C,.¢alkyl)aminoC;.galkylamino; arylsulfonyl; arylsulfonylamino; ‘ aryloxy; arylCs.¢alkenediyl; di(C, .ealkyl)amino; di(C.¢alkyl)aminoC.galkyl; di(C,.¢alkyl)aminoC ¢alkyl(C;_galkyl)aminoC; galkyl; cyano; thiophenyl; thiophenyl substituted with di(C.galkyl)aminoC;_galkyl(C;.galkyl)aminoC 1-6alkyl, di(C_galkyl)aminoCj.galkyl,
C.¢alkylpiperazinylCj_galkyl or di(hydroxyC,.galkyl)aminoC;_galkyl; furanyl; imidazolyl; C_alkyltriazolyl; tetrazolyl; pyrrolidinyl; piperidinylCi.galkyloxy, morpholinyl; Cy.¢alkylmorpholinyl; morpholinylCj.alkyloxy; morpholinylCy_galkyl; Cy ¢alkylpiperazinyl; Ci.salkylpiperazinylC;_salkyloxy;
C;.¢alkylpiperazinylCq_galkyl; C,.¢alkylpiperazinylsulfonyl; aminosulfonylpiperazinylC,.galkyloxy; aminosulfonylpiperazinyl; aminosulfonylpiperazinylCj.salkyl; di(C_galkyl)aminosulfonylpiperazinyl; di(C;.galkyl)aminosulfonylpiperazinylC, galkyl; hydroxyC;.ealkylpiperazinyl, hydroxyC_galkylpiperazinylCy_galkyl; C;-galkyloxypiperidinyl;
C.salkyloxypiperidinylC_salkyl; hydrox yC).¢alkyloxyC.alkylpiperazinyl; hydrox yCj.salkyloxyC_ealkylpiperazinylC,.ealkyl; (hydroxyCj_¢alkyl)(Ci.galkyl)amino; (hydroxyCj.ealkyl)(Cy .alkyl)aminoC;_galkyl; pyrrolidinylC .¢alkyloxy; pyrazolyl; thiopyrazolyl; pyrazolyl substituted with two substituents selected from C,.galkyl or trihaloCy.galkyl; pyridinyl; pyridinyl substituted with Cy.galkyloxy or aryl; pyrimidinyl; quinolinyl; indole; phenyl; phenyl substituted with one, two or three substituents independently selected from halo, amino, C;.ealkyl, Cj.¢alkyloxy, hydroxyCj alkyl; trifluoromethyl, trifluoromethyloxy, hydroxyCi_4alkyloxy, C.salkyloxyCj.salkyloxy, aminoCj_salkyloxy, di(Cj.4alkyl)aminoCy.4alkyloxy, di(C,_salkyl)amino, di(C4alkyl)aminoC alkyl, di(C.4alkyl)aminoC; 4alkyl(C.salkyl)aminoC_salkyl, piperidinylCj.4alkyloxy, pyrrolidinylCy_salkyloxy; aminosulfonylpiperazinyl, aminosulfonylpiperazinylC, 4alkyl, di(C_salkyl)aminosulfonylpiperazinyl, di(C.salkyl)aminosulfonylpiperazinylCy_4alkyl, hydroxyC,.salkylpiperazinyl, hydroxyC_salkylpiperazinylC_salkyl, Ci-salkyloxypiperidinyl,
C,.salkyloxypiperidinylCy_salkyl, hydroxyC, _salkyloxyCj_4alkylpiperazinyl, hydrox yCj.salkyloxyCj.salkylpiperazinylCj_salkyl, (hydrox yCj.4alkyl)(Cj.salkyl)amino, (hydrox yC).4alkyl)(Cj_galkyl)aminoC;_salkyl, ) 35 pyrrolidinylC;_salkyloxy, morpholinylC;_4alkyloxy, morpholinylC;_salkyl,
C,.4alkylpiperazinyl, Cj_salkylpiperazinylC, 4alkyloxy,
C.salkylpiperazinylC_4alkyl, hydroxyCj.salkylamino, di(hydroxyC)_4alkyl)amino,
di(C,4alkyl)aminoC,_4alkylamino, aminothiadiazolyl, aminosulfonylpiperazinylCj_salkyloxy, or thiophenylC) 4alkylamino. ‘ A further group of preferred compounds consists of those compounds of formula (I) wherein t is 0; : R' is -C(O)NRPR®, -C(0)-C: calkanediylSR'’, -NR''C(O)N(OH)R"*, _NR''C(O)C, ¢alkanediylSR', -NR''C(O)C=N(OH)R '® or another Zn-chelating- group wherein R® and R’ are each independently selected from hydrogen, hydroxy, hydroxyC).¢alkyl or aminoCi alkyl; R%is hydrogen, halo, hydroxy, amino, nitro, C,.¢alkyl, C,salkyloxy, trifluoromethyl or di(C,.¢alkyl)amino,
R* is hydrogen, hydroxy, amino, hydroxyC;.ealkyl, Ci.¢alkyl,
C,.¢alkyloxy, arylCy.ealkyl, aminocarbonyl, aminoCi_galkyl,
C.¢alkylaminoCi.galkyl or di(C,.galkyl)aminoCj_galkyl;
R’is hydrogen; —® is a radical selected from (a-1), (a-3), (a-4), (2-5), (a-6), (a-7), (2-8), (2-9), (2-10), (a-1 1), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (2-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-28), (a-29), (2-30), (a-31), (a-32), (2-33), (a-34), (a-35), (2-36), (a-37), (a-38), (a-39), (a-40), (a-41), (2-42), (a-44), (a-45), (a-46), (2-47), (a-48) or (a-51); each s is independently 0, 1,2, 3 or 4;
RS is hydrogen; halo; hydroxy; amino; nitro; trihaloC;_galkyl; trihaloCj.galkyloxy;
C,.¢alkyl; Cj.salkyloxy; C.salkylcarbonyl; C,.¢alkyloxycarbonyl;
C,.¢alkylsulfonyl; hydroxyCj.galkyl; aryloxy; di(Cy.galkyl)amino; cyano; thiophenyl; furanyl; furanyl substituted with hydroxyCj.ealkyl; benzofuranyl; imidazolyl; oxazolyl; oxazoly! substituted with aryl and Cygalkyl,
C,.galkyltriazolyl; tetrazolyl; pyrrolidinyl; pyrrolyl; morpholinyl;
C1.¢alkylmorpholinyl; piperazinyl; C 1-6alkylpiperazinyl; hydroxyC.salkylpiperazinyl; C.¢alkyloxypiperidinyl; pyrazoly; pyrazolyl substituted with one or two substituents selected from Cj_galkyl or trihaloCy.galkyl; pyridinyl; pyridinyl substituted with C;.salkyloxy, aryloxy or aryl; pyrimidinyl; . _quinolinyl; indole; phenyl; or phenyl substituted with one or two substituents independently selected from halo, Cy.¢alkyl, C;.¢alkyloxy or trifluoromethyl; and
R’ is hydrogen; halo; hydroxy; amino; nitro; trihaloC.galkyl; trihaloC; galkyloxy;
C.galkyl; Cy.ealkyloxy; Cj_galkylcarbonyl; C.¢alkyloxycarbonyl; Cy galkylsulfonyl, hydroxyC;_ealkyl; aryloxy; di(Cy.¢alkyl)amino; cyano; pyndinyl; phenyl; or phenyl substituted with one or two substituents independently selected from halo, Cy_galkyl,
C,.¢alkyloxy or trifluoromethyl. : A group of more preferred compounds consists of those compounds of formula (I) whereinnis0, Lor 2; tis0, 1,2 or 3; cach Qis > ;R! is ~C(O)NH(OH) or ’ —NR''C(O)C=N(OH)R'’ wherein R'? is arylC, ¢alkyl and R'! is hydrogen; Ris hydrogen, C)alkyl or naphtalenylsulfonylpyrazinyl; each R’ independently represents a hydrogen atom; R* is hydrogen, hydroxy, hydroxyC,_.ealkyl or
Ci.¢alkyloxy; Ris hydrogen, C;_galkyl, hydroxyCj_ealkyl or C;_salkyloxyC,_ ealkyl; —® is a radical selected from (a-1), (a-7) or (a-20); each s is independently O or 1; each R® is independently selected from hydrogen; thiophenyl; furanyl; benzofuranyl; phenyl; or phenyl substituted with one substituents independently selected from C.galkyl, Cy.galkyloxy, hydroxyCj_4alkyl, C;_salkylsulfonyl or di(C;_4alkyl)amino and each R’ is independently selected from hydrogen.
A group of even more preferred compounds consists of those compounds of formula (I) wherein nis 1 or 2; tis 0,1, 2 or 3; each Q is —< : R! is -C(O)NH(OH); R%is hydrogen or Cy_salkyl; each R? independently represents a hydrogen atom; R*is hydrogen; R’ is hydrogen or C;_galkyloxyCi.salkyl; —® is a radical selected from (a-1) or (a-20); each s is independently 0 or 1; and each R® is independently selected from hydrogen; thiophenyl; furanyl; benzofuranyl; phenyl; or phenyl substituted with one substituents independently selected from Cj.galkyl, Cj_salkyloxy, hydroxyCj.4alkyl or di(Cj_4alkyl)amino.
Most preferred compounds are compounds No. 13, No. 15, No. 2, No. 5, No. 21, No. 4,
No. 24, No. 32, No. 26, No. 36, No. 38, No. 39, No. 40, No. 41, No. 42, No. 43, No. 44 and No. 35. or Q oH of os =N
Co. No. 13 Co. No. 15
CRs 7 aR hee SaUee
H NN
Ho” LU Ho T
Ho" ZN ° Oo SR
Co. No. 2 Co. No. 5 . NTH NTI
SI ey " Sh CO
AL AAT
[8] [8] .0.7 CH;0H; Co. No. 21 Co. No. 4
O gos Wea - ~ N.
TCD | oot 0.23 C¢H,40; Co. No. 24 .0.82 C,HF;0,; .0.82 H,0; Co. No. 32 ?
BN OO
Sean A,
A
NA No .0.85 C;HF;0, .1.11 H,0 Co. No. 26 Co. No. 36
JN AN oa CHO, 0 wit CO, 0
S<o sSo \
O< J a! &
Co. No. 38 Co. No. 39

Claims (1)

  1. Claims
    1. A compound of formula (I), . rR? i R3 t R ~X / (GH), — \ Z—(CR))—N—5 — A ) (0 AE AN g R? the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo- chemically isomeric forms thereof, wherein : nis0,]1,2or3 and when nis 0 then a direct bond is intended; tis 0,1, 2, 3 or 4 and when t is 0 then a direct bond is intended; each Q is nitrogen or a each X is nitrogen or BY ; each Y is nitrogen or Ss ; —CH”™ each Zis nitrogen or ~ R' is -C(O)NR®R®, -N(H)C(O)R'’, -C(0)-C, salkanediylSR'’, -NR"'C(O)N(OH)R, -NR''C(0)C; alkanediylSR'®, -NR''C(O)C=N(OH)R'® or another Zn-chelating- group wherein R® and R® are each independently selected from hydrogen, hydroxy, C,salkyl, hydroxyC,salkyl, aminoC, ¢alkyl or aminoaryl, R'is independently selected from hydrogen, C,.alkyl, C;.salkylcarbonyl, arylC,. alkyl, Cy.salkylpyrazinyl, pyridinone, pyrrolidinone or methylimidazolyl; R'' is independently selected from hydrogen or C,_¢alkyl; : R?is hydrogen, halo, hydroxy, amino, nitro, Cy.alkyl, C;.salkyloxy, trifluoromethyl, di(C,_salkyl)amino, hydrox yamino or naphtalenylsulfonylpyrazinyl, each R’ independently represents a hydrogen atom and one hydrogen atom can be replaced by a substituent selected from aryl;
    R%is hydrogen, hydroxy, amino, hydroxyCj.galkyl, Cigalkyl, C_galkyloxy, arylC,_galkyl, aminocarbonyl, hydroxycarbonyl, aminoC;_galkyl, aminocarbonylCy.galkyl, hydrox ycarbonylC;_galkyl, hydroxyaminocarbonyl, : C,.salkyloxycarbonyl, Cy.galkylaminoCj.¢alkyl or di(C;.galkyl)aminoC,_galkyl;
    . R® is hydrogen, Cj_galkyl, Cs.jocycloalkyl, hydroxyC,ealkyl, C}.¢alkyloxyC,_galkyl, di(C.¢alkyl)aminoC,_galkyl or aryl; © is a radical selected from vil ah ah vil S N, / RCI GEES GI t ZF FZ FF (a-1) (a-2) (a-3) (a4) s Rs Ds Ns +4 ea y 17 NH L_o AY, (a-5) (2-6) @7) (2-8) Ds Rs Ms Ms S, S, 0, 0} N — 7 — $7 (a-9) (a-10) (a-11) (a-12) ’) S 7 H R )s 7s H Ms oO \ i A A A VEC — pu LU; y (@-13) (a-14) (a-15) (a-16)
    7 o) \ a )s ; “ i ve s H,C NY N 0 )s Tl )s | = A A ~ N /'NH \ \ To (a-17) (a-18) N (a-19) N (2-20) ve K RY; rR) , J | AS Na | AS Na \G F NF a N” (a-21) (a-22) (a-23) (a-24)
    7), bY 6) . LY rr ZF = | N—~# Pav |® x \ A oO N H (a-25) (a-26) (@-27) (a-28) a Wal Vik va oY vo Un Un N x Ad ZA ~N 20 (a-29) (a-30) (a-31) (a-32) "x | Rs o Rg \ Ds SN FA SK NF Cr >=0 (1 J C17] ZN NZ TS N ~~ NX H (a-33) (a-34) (a-35) (2-36) Ms DY DY bX FAA N ZF N 0 ZZ N pY, (a-37) (a-38) (2-39) (a-40)
    oo Vik 1 RY), F Na a ; (a-41) (a-42) (a-43) (a-44) : 0 (RY), 0 (RY), 0 RY) Ms Yow WE oH za CL AY GE Ge (a-45) (a-46) (2-47) (2-48) Ms RY), bY AL S p% Q, “NT “4 x N | NPL (a-49) (a-50) (a-51) wherein each s is independently 0, 1, 2, 3, 4 or 5; each R® and R are independently selected from hydrogen; halo; hydroxy; amino; nitro; trihaloC|.¢alkyl; trihaloC;_galkyloxy; C\.ealkyl; C;.galkyl substituted with aryl and
    Cs.iocycloalkyl; Cy galkyloxy; Cy.salkyloxyCi.galkyloxy; Ci .ealkylcarbonyl; Ci-ealkyloxycarbonyl; Cy_galkylsulfonyl; cyanoCj_galkyl; hydroxyCj_galkyl; hydroxyCj_galkyloxy; hydroxyC,.salkylamino; aminoCj_galkyloxy; di(C,.galkyl)aminocarbonyl; di(hydroxyC_galkyl)amino; (aryl)(C_galkyl)amino; di (C1.¢alkyl)aminoCy_galkyloxy; di(Cy_salkyl)aminoC_galkylamino; di(C.¢alkyl)aminoC_galkylaminoC_galkyl; arylsulfonyl; arylsulfonylamino; aryloxy; aryloxyC_galkyl; arylCy._¢alkenediyl, di(C,_galkyl)amino; di(C.galkyl)aminoC_galkyl; di(Cy.ealkyl)amino(C;_galkyl)amino; di(C 1-6alkyl)amino(C _galkyl)aminoC _galkyl; di(Cy_galkyl)aminoC).¢alkyl(C,_galkyl)amino; di(C_galkyl)aminoC.galkyl(C 1-6alkyl)aminoC_galkyl; aminosulfonylamino(C)_galkyl)amino; aminosulfonylamino(C _galkyl)aminoC 1-6alkyl; di(Cy_galkyl)aminosulfonylamino(C 1-6alkyl)amino; di(C,.alkyl)aminosulfonylamino(C.¢alkyl)aminoC,_galkyl; cyano; thiophenyl; thiophenyl substituted with di(Cy.galkyl)aminoC_alkyl(C,.galkyl)aminoC,_galkyl, di(C.salkyl)aminoC;_galkyl, Ci.6alkylpiperazinylC, _galkyl, hydroxyC,_galkylpiperazinylC_galkyl, hydroxyCi_ealkyloxyCy_salkylpiperazinylC)_galkyl,
    di(C;_galkyl)aminosulfonylpiperazinylC,_galkyl,
    Ci.ealkyloxypipendinyl, Cy_galkyloxypiperidinylC;_galkyl, morpholinylCy_galkyl, hydrox yCj.¢alkyl(C;.¢alkyl)aminoCy_¢alkyl, or di(hydroxyCj_galkyl)aminoC,_galkyl; furanyl; furanyl substituted with hydroxyCj_salkyl; benzofuranyl; imidazolyl; oxazolyl; oxazolyl substituted with aryl and C;_galkyl; C.¢alkyltriazolyl; tetrazolyl, : pyrrolidinyl; pyrrolyl; piperidinylC;_galkyloxy; morpholinyl; C;_galkylmorpholinyl; morpholinylC,_galkyloxy; morpholinylC,_galkyl; morpholinylC;_galkylamino; morpholinylC;_galkylaminoC,_galkyl; piperazinyl; C|_galkylpiperazinyl;
    C.salkylpiperazinylC,_galkyloxy; piperazinylC,_galkyl; naphtalenylsulfonylpiperazinyl; naphtalenylsulfonylpiperidinyl; naphtalenylsulfonyl;
    C,.ealkylpiperazinylC)_galkyl; C_galkylpiperazinylC;_galkylamino;
    Ci.ealkylpiperazinylCj_galkylaminoCj_galkyl; Cy salkylpiperazinylsulfonyl; aminosulfonylpiperazinylC,_salkyloxy; aminosulfonylpiperazinyl; : aminosulfonylpiperazinylCy.galkyl; di(C,.galkyl)aminosulfonylpiperazinyl; di(C;.¢alkyl)aminosulfonylpiperazinylC,_galkyl; hydroxyCj.¢alkylpiperazinyl; hydroxyC,_salkylpiperazinylC,_galkyl; C;.galkyloxypiperidinyl;
    Ci.ealkyloxypiperidinylCj_galkyl; piperidinylaminoC,_galkylamino; piperidinylaminoC,_galkylaminoC,_galkyl;
    (Cy._esalkylpiperidinyl)(hydroxyC, salkyl)aminoC_galkylamino; (Ci-ealkylpiperidinyl)(hydroxyC; ¢alkyl)aminoC;.galkylaminoC;_galkyl; hydroxyCj_salkyloxyCj.ealkylpiperazinyl; hydroxyCj_galkyloxyC;.ealkylpiperazinylC; galkyl; (hydroxyCi.¢alkyl)(Cj.galkyl)amino; (hydroxyCi.ealkyl)(C;.salkyl)aminoC _galkyl; hydroxyCj.galkylaminoCj_galkyl; di(thydroxyC,_salkyl)aminoC_galkyl; pyrrolidinylCy_galkyl; pyrrolidinylCj.¢alkyloxy; pyrazolyl; thiopyrazolyl; pyrazolyl substituted with two substituents selected from C)_galkyl or trihaloCy_galkyl; pyridinyl; pyridinyl substituted with C,_salkyloxy, aryloxy or aryl; pyrimidinyl, tetrahydropyrimidinylpiperazinyl; tetrahydropyrimidinylpiperazinylCj_gsalkyl; quinolinyl; indole; phenyl; phenyl substituted with one, two or three substituents independently selected from halo, amino, nitro, Cy_galkyl, C;_galkyloxy, hydroxyCj_salkyl, trifluoromethyl, trifluoromethyloxy, hydroxyC;_salkyloxy,
    Cj.4alkylsulfonyl, C,.4alkyloxyC;_galkyloxy, C;_salkyloxycarbonyl, : aminoCj_salkyloxy, di(C_4alkyl)aminoC,_salkyloxy, di(C;_4alkyl)amino, di(C,_4alkyl)aminocarbonyl, di(C;.4alkyl)aminoC; alkyl, ’ 35 di(C,.4alkyl)aminoC,_salkylaminoC,_4alkyl, di(C,_salkyl)amino(C;.salkyl)amino, di(C;_4alkyl)amino(C;.4alkyl)aminoC;_4alkyl, di(C,_salkyl)aminoC,_4alkyl(C;_4alkyl)amino, di(C.4alkyl)aminoC;_qalkyl(C_4alkyl)aminoC,_salkyl,
    aminosulfonylamino(C;_4alkyl)amino, aminosulfonylamino(C;_4alkyl)aminoCj_4alkyl, di(C,_qalkyl)aminosulfonylamino(C;_4alkyl)amino, di(C,_4alkyl)aminosulfonylamino(C;.4alkyl)aminoC,_galkyl, cyano, piperidinylCj_salkyloxy, pyrrolidinylC;_salkyloxy, aminosulfonylpiperazinyl, aminosulfonylpiperazinylCj_salkyl, di(C;.4alkyl)aminosulfonylpiperazinyl, di(Cy_salkyl)aminosulfonylpiperazinylC_salkyl, hydroxyC,_salkylpiperazinyl, hydrox yCj_salkylpiperazinylC)_salkyl, C;_salkyloxypiperdinyl,
    Ci.salkyloxypiperidinylCj_4alkyl, hydroxyC,_salkyloxyC;_salkylpiperazinyl, hydroxyC;_salkyloxyC;.4alkylpiperazinylC;_4alkyl, (hydrox yCj.4alkyl)(C,.4alkyl)amino, (hydroxyCj_salkyl)(Cj.4alkyl)aminoC)_salkyl, di(hydroxyCj.4alkyl)amino, di(hydroxyC_salkyl)aminoC;_4alkyl, furanyl, furanyl substituted with -CH=CH-CH=CH-, pyrrolidinylC_salkyl, pyrrolidinylC,_salkyloxy, morpholinyl, morpholinylC;_4alkyloxy, morpholinylC,_salkyl, morpholinylC,_salkylamino, morpholinylC;_4alkylaminoC;_4alkyl, piperazinyl,
    Ci.4alkylpiperazinyl, Ci salkylpiperazinylC,_4alkyloxy, piperazinylC,_salkyl,
    Ci.salkylpiperazinylCy_4alkyl, Cy_salkylpiperazinylC_4alkylamino, Ci-4alkylpiperazinylCi_salkylaminoCj_galkyl, tetrahydropyrimidinylpiperazinyl, tetrahydropyrimidinylpiperazinylC;_4alkyl, piperidinylaminoCj_salkylamino, piperidinylaminoC;_4alkylaminoC,_salkyl, (C-salkylpiperidinyl)(hydroxyC, 4alkyl)aminoC;_salkylamino, (Cj-4alkylpiperidinyl)(hydroxyC,alkyl)aminoC;_salkylaminoC;_4alkyl, pyndinylC;_salkyloxy, hydroxyCi.salkylamino, hydroxyC_salkylaminoC;_salkyl, di(Cy.4alkyl)aminoCj_salkylamino, aminothiadiazolyl, aminosulfonylpiperazinylC,_4alkyloxy, or thiophenylC,_4alkylamino; each R® and R can be placed on the nitrogen in replacement of the hydrogen; aryl in the above is phenyl, or phenyl! substituted with one or more substituents each independently selected from halo, C,_¢alkyl, Cj.alkyloxy, trifluoromethyl, cyano or hydroxycarbonyl.
    2. A compound as claimed in claim 1 whereinnis 0, 1 or 2; tis 0, 1, 2 or 3; each Q is TS; Ris ~C(O)NH(OH) or -NR! 'C(0)C=N(OH)R'"® wherein R'is arylC, alkyl and R"' is hydrogen; R? is hydrogen, Ci.ealkyl or naphtalenylsulfonylpyrazinyl; each R? independently represents a hydrogen atom; R* is hydrogen, hydroxy, hydroxyC;.galkyl or Ci.¢alkyloxy; R’ is hydrogen, C,. salkyl, hydroxyCi_galkyl or C;_galkyloxyC_galkyl; —® is a radical selected from (a-1), (a-7) or (a-20); each s is independently 0 or 1; each RC is independently : selected from hydrogen; thiophenyl; furanyl; benzofuranyl; phenyl; or phenyl substituted with one substituents independently selected from C;_galkyl,
    C1.¢alkyloxy, hydroxyC)_4alkyl, C).salkylsulfonyl or di(Cj_salkyl)amino and each R’ is independently selected from hydrogen.
    3. A compound according to claim 1 wherein tis 0; R' is —C(O)NR®R®, -C(0)-C, salkanediylSR'®, -NR''C(O)N(OH)R'’, -NR''C(0)C,.¢alkanediylSR'?, -NR''C(O)C=N(OH)R '® or another Zn-chelating- group wherein R® and R® are each independently selected from hydrogen, hydroxy, hydroxyC,.salky! or aminoC, alkyl; R? is hydrogen, halo, hydroxy, amino, nitro, Cy.salkyl, Cy.¢alkyloxy, trifluoromethyl or di(C, ¢alkyl)amino; R* is hydrogen, hydroxy, amino, hydroxyCj.¢alkyl, Cy.ealkyl, C1-ealkyloxy, arylC,_galkyl, aminocarbonyl, aminoC;_salkyl,
    C.¢alkylaminoCy_galkyl or di(Cj.galkyl)aminoCj_salkyl; R’ is hydrogen; —® is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (2-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (2-23), (a-24), (a-25), (a-26), (a-28), (a-29), (a-30), (a-31), (2-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42), (a-44), (a-45), (a-46), (a-47), (a-48) or (a-51); each s is independently 0, 1, 2, 3 or 4, R® is hydrogen; halo; hydroxy; amino; nitro; trihaloC .ealkyl; trihaloC_galkyloxy;
    C,.salkyl; Cy.galkyloxy; Cy.¢alkylcarbonyl; Ci.galkyloxycarbonyl;
    Ci.salkylsulfonyl; hydroxyCy.galkyl; aryloxy; di(Cj.galkyl)amino; cyano; thiophenyl; furanyl; furanyl substituted with hydroxyCj_salkyl; benzofuranyl; imidazolyl; oxazolyl; oxazolyl substituted with aryl and Cj.galkyl;
    C.¢alkyltriazolyl; tetrazolyl; pyrrolidinyl; pyrrolyl; morpholinyl;
    C;.salkylmorpholinyl; piperazinyl; Cy salkylpiperazinyl; hydroxyC).¢alkylpiperazinyl; C;.¢alkyloxypiperidinyl; pyrazoly; pyrazoly! substituted with one or two substituents selected from C_galkyl or trihaloC;_galkyl; ) pyridinyl; pyridinyl substituted with Cy_galkyloxy, aryloxy or aryl; pyrimidinyl; quinolinyl; indole; phenyl; or phenyl substituted with one or two substituents independently selected from halo, Cj_galkyl, C).¢alkyloxy or trifluoromethyl; and R’ is hydrogen; halo; hydroxy; amino; nitro; trihaloC).galkyl; trihaloC) _galkyloxy;
    C.salkyl; Cy galkyloxy; Cj.ealkylcarbonyl; C;_galkyloxycarbonyl; Cy galkylsulfonyl,
    hydroxyCi_salkyl; aryloxy; di(C;.galkyl)amino; cyano; pyridinyl; phenyl; or phenyl substituted with one or two substituents independently selected from halo, C;_galkyl,
    Ci.¢alkyloxy or trifluoromethyl.
    4. A compound as claimed in claim 1 wherein : R® and R® are each independently selected from hydrogen, hydroxy, hydroxyC,_.salkyl, aminoC,_¢alkyl or aminoaryl; R® is hydrogen, Cy_galkyl, Cs. jocycloalkyl, hydroxyC,.salkyl, Cy_galkyloxyC_galkyl or di(C,.galkyl)aminoC,_galkyl, —(® is a radical selected from (a-1), (a-2), (a-3), (a-4), (2-5), (2-6), (2-7), (a-8), (2-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (2-27), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (2-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42) (a-43) or (a-44); eachR®andR’ are independently selected from hydrogen; halo; hydroxy; amino; nitro; trihaloCj_galkyl; trihaloCj_galkyloxy; Cj.galkyl; Cj.¢alkyloxy;
    Ci.6alkyloxyC_galkyloxy; C.galkylcarbonyl; C.galkylsulfonyl; cyanoCy.galkyl; hydroxyC,_salkyl; hydroxyCj_galkyloxy; hydroxyC;_galkylamino; aminoCj_galkyloxy; di(Cy.galkyl)aminocarbonyl; dithydroxyC;.galkyl)amino; arylCy_galkyl)amino; di(C)_galkyl)aminoC;.galkyloxy; di(C,_salkyl)aminoC;_galkylamino; arylsulfonyl; arylsulfonylamino; aryloxy; arylCj_galkenediyl; di(C;.¢alkyl)amino; di(Cy.¢alkyl)aminoCy.galkyl; di(C;.alkyl)aminoCj.¢alkyl(C;.¢alkyl)aminoC_galkyl; cyano; thiophenyl; thiophenyl substituted with di(C,.galkyl)aminoC,_galkyl(C_galkyl)aminoC_galkyl, di(Cy.galkyl)aminoC,_galkyl,
    C,.¢alkylpiperazinylC,_galkyl or di(hydroxyC,.salkylaminoCj_galkyl; furanyl; imidazolyl; Cy_galkyltriazolyl; tetrazolyl; pyrrolidinyl; piperidinylC,_galkyloxy; morpholinyl; Cj_galkylmorpholinyl; morpholinylC,;_salkyloxy; morpholinylC,_ealkyl; C,.salkylpiperazinyl; C;_salkylpiperazinylC,_galkyloxy;
    Ci.ealkylpiperazinylC,_galkyl; Cj.¢alkylpiperazinylsulfonyl; aminosulfonylpiperazinylC, galkyloxy; aminosulfonylpiperazinyl; aminosulfonylpiperazinylC_galkyl; di(C;.¢alkyl)aminosulfonylpiperazinyl, di(C;.ealkyl)aminosulfonylpiperazinylCy.galkyl; hydroxyC,_salkylpiperazinyl; hydrox yCj_salkylpiperazinylC)_galkyl; C;.¢alkyloxypiperidinyl;
    Ci.ealkyloxypiperidinylCj_galkyl; hydroxyC, galkyloxyC;_ ¢alkylpiperazinyl, hydroxyCj.salkyloxyC,_¢alkylpiperazinylC;_galkyl;
    (hydroxyCi.galkyl)(C.galkyl)amino; (hydroxyC.ealkyl)(C;_galkyl)aminoC _galkyl; pyrrolidinylCy.¢alkyloxy; pyrazolyl; thiopyrazolyl; pyrazolyl substituted with two substituents selected from Cy _galkyl or trihaloCj_galkyl; pyndinyl; pyridinyl } substituted with Cj.galkyloxy or aryl; pyrimidinyl; quinolinyl; indole; phenyl; phenyl substituted with one, two or three substituents independently selected from halo,
    . amino, Cy.galkyl, C;.¢alkyloxy, hydroxyCj.salkyl, trifluoromethyl, trifluoromethyloxy, hydroxyC,.salkyloxy, C;.salkyloxyCj.4alkyloxy, aminoC)_4alkyloxy, di(C;_4alkyl)aminoC 4alkyloxy, di(C,_salkyl)amino, di(Cj.salkyl)aminoC_salkyl, di(C,_4alkyl)aminoCj_4alkyl(C;_salkyl)aminoCj_salkyl, piperidinylCj_salkyloxy, pyrrolidinylC;_salkyloxy, aminosulfonylpiperazinyl, aminosulfonylpiperazinylCj alkyl, di(C,.salkyl)aminosulfonylpiperazinyl, di(Cj_salkyl)aminosulfonylpiperazinylC;_4alkyl, hydroxyCi_salkylpiperazinyl, hydroxyC,_salkylpiperazinylC,_4alkyl, C;.salkyloxypiperidinyl, CalkyloxypiperidinylC;_salkyl, hydroxyCj_salkyloxyC,_salkylpiperazinyl, hydroxyCj_4alkyloxyCj 4alkylpiperazinylC,_salkyl, (hydroxyC.4alkyl)(C;.4alkyl)amino, (hydroxyCj.salkyl)(C.salkyl)aminoC,_salkyl, pyrrolidinylC;_4alkyloxy, morpholinylC;_salkyloxy, morpholinylC;_salkyl,
    C,.4alkylpiperazinyl, C.4alkylpiperazinylC,_galkyloxy, C;_sqalkylpiperazinylCj_salkyl, hydrox yCj_salkylamino, dithydroxyCj_salkyl)amino, di(C;qalkyl)aminoC_4alkylamino, aminothiadiazolyl, aminosulfonylpiperazinylCj4alkyloxy, or thiophenylC;_salkylamino.
    5. A compound as claimed in claim 1 and 2 wherein nis 1 or 2; tis 0, 1, 2 or 3; each Qis —< : R! is —C(O)NH(OH); R? is hydrogen or C.galkyl; each R* independently represents a hydrogen atom, R* is hydrogen; Ris hydrogen or Ci-salkyloxyC.galkyl; —® is a radical selected from (a-1) or (a-20); each s is independently O or 1; and each R%is independently selected from hydrogen; thiophenyl; furanyl; benzofuranyl; phenyl; or phenyl substituted with one substituents independently selected from C,_galkyl, C;¢alkyloxy, hydroxyC,_salkyl or di(Cy.salkyl)amino.
    6. A compound according to claim 1, 2 and 5 selected from compounds No. 13,
    . No. 15, No. 2, No. 5, No. 21, No. 4, No. 24, No. 32, No. 26, No. 36, No. 38, No. 39,
    No. 40, No. 41, No. 42, No. 43, No. 44 and No. 35.
    H Yi Sf 7 \ = ? » OO (7 OO OH . ) ee]
    Co. No. 13 Co. No. 15 Os420 i TCO Spe L(YTTTCC Negose Ho” o ALA 0 _ oy
    Co. No. 2 Co. No. 5 NTI N~ JHC Negiise LC 0 | a HO” HO” 0 0
    0.7 CH;0H; Co. No. 21 Oo “A R oY H I | = gy Wea - S< N C0 | oot
    0.23 C¢H,40; Co. No. 24 .0.82 C,HF;0, .0.82 H,0O; Co. No. 32 7 cotro On, NS HN At OO N~# Ne [or CH, .0.85 C,HF50; 1.11 HO; Co. No. 26 Co. No. 36 0 N 0 aR AR wot OM OO, w\ LP HNP S=0 S=q OO 2a! O
    Co. No. 38 Co. No. 39
    / | bad ot On, 0 HO—NH Be On 0 so H S$ 4 ose
    Co. No. 40 Co. No. 41 Q, 7 \ SH oO AL 5 HO—NH =N On, A» S=q S=q SO
    Co. No. 42 Co. No. 43 CO oy HO—NH “=x nN, L f i @) N (| co C—O CO N O_
    Co. No. 35
    7. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 1 to 6.
    8. A process of preparing a pharmaceutical composition as claimed in claim 7 wherein the pharmaceutically acceptable carriers and a compound as claimed in claim 1 to 6 are intimately mixed.
    9. A compound as claimed in any of claims 1 to 6 for use as a medicine.
    10. Use of a compound as claimed in any of claims 1 to 6 for the manufacture of a medicament for the treatment of proliferative diseases.
    11. A process for preparing a compound as claimed in claim 1, characterized by reacting an intermediate of formula (II) with an appropriate acid, such as for example, trifluoro acetic acid, yielding a hydroxamic acid of formula (I-a), wherein R' is -C(O)NH(OH)
    of ® : PCT/EP03/02517 -88- ) 4 CF;COOH O° Ae ew vt N Z—(CR’)p)—N— H ( - WO) i= R? oo 4 an so. Jo [TCHR OR P N \y an Was LR —(» . | R? i : (1-a)
    12. A method of detecting or identifying a HDAC in a biological sample comprising detecting or measuring the formation of a complex between a labelled compound as defined in claim (I) and a HDAC.
    13. A combination of an anti-cancer agents and a HDAC inhibitor as claimed in any of claims 1 to 6.
    14. A substance or composition for use in a method for the treatment of proliferative diseases, said substance or composition comprising a compound as claimed in any of claims 1 to 6, and said method comprising administering said substance or composition.
    15. A compound as claimed in any one of claims 1 to 6 or 9, substantially as ‘herein described and illustrated.
    16. A composition as claimed in claim 7, substantially as herein described and illustrated.
    17. A process as claimed in claim 8 or claim 11, substantially as herein described and illustrated.
    18. Use as claimed in claim 10, substantially as herein described and illustrated.
    19. A method as claimed in claim 12, substantially as herein described and illustrated. + 20. A combination as claimed in claim 13, substantially as herein described and illustrated. AMENDED SHEET
    ; . . < PCT/EP03/02517 89
    21. A substance or composition for use in a method of treatment as claimed in claim 14, substantially as herein described and illustrated.
    22. A new compound, a new composition, a new process for preparing a composition, a new process for preparing a compound, a new use of a compound as claimed in any one of claims 1 to 6, a new detection or identification method, a new combination, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET
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